Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). HCV is a major pathogen transmitted via infected blood that infects some 170 million people around the world. The infection can remain hidden without showing symptoms for years, and many people don't know they are infected.
A feature of HCV is that its course is unpredictable. The virus causes chronic (long-term) infections in 60% to 85% of infected individuals. From 20-50% of these infected individuals develop progressive liver disease, leading ultimately to liver cirrhosis, liver failure and/or hepatocellular carcinoma. Liver damage from chronic hepatitis C virus infection is now the most common cause of liver transplantation in the US. However, a small minority of infected individuals seem to have sufficient immunity that they clear the virus soon after infection.
HCV is a positive-sense RNA virus belonging to the Flaviviridae family. It encodes a single polyprotein of ˜3,000 amino acids (aa). Through the action of a combination of host and viral proteases, the polyprotein is cleaved into structural proteins (core, E1, E2, and p′7) and nonstructural proteins (NS2-NS5B). The two envelope glycoproteins, E1 and E2, are believed to form heterodimers/oligomers on the surface of HCV particles that participate in the process of cell entry (Bartosch, B. et al. 2003 J Exp Med 197:633-642).
HCV infection is treated with antiviral medications, e.g. pegylated interferon administered alone or in combination with ribavirin. Combination therapy with pegylated interferon and ribavirin is now successful in about half of the cases, but it is currently prohibitively expensive, requires long-term treatment, and is associated with serious side effects. In much of the world, such treatments are not economically feasible. New direct-acting antiviral drugs such as protease and polymerase inhibitors, either with or without interferon and/or ribavirin, have the potential to increase the response rate and to decrease the duration of treatment. However, these drugs may also have significant side effects and are extremely expensive. Two protease inhibitors are now licensed for use in combination with interferon and ribavirin although the treatment costs are between $26,000-$49,000 per patient depending on the treatment duration, in addition to the costs for pegylated interferon and ribavirin (Tungol, A. et al. J Manag Care Pharm 2011; 17:685-94).
There are at least six known genotypes and more than 50 subtypes of HCV. Specific genotypes are in general located in distinct geographical locations, while a small number of subtypes (1a, 1b, 2a and 3a) have recently become more widely distributed and are associated with modern practices such as medical injections, blood products and intravenous drug use. Knowing the genotype can help predict the likelihood of treatment response and, in many cases, determine the duration of treatment. Patients with genotypes 2 and 3 are almost three times more likely than patients with genotype 1 to respond to therapy with alpha interferon or the combination of alpha interferon and ribavirin. When using combination therapy, the recommended duration of treatment depends on the genotype. For patients with genotypes 2 and 3, a 24-week course of combination treatment is adequate, whereas for patients with genotype 1, a 48-week course is recommended
Although a vaccine that prevents and treats HCV infection is urgently required, no vaccine is currently available for HCV. A therapeutic vaccine would be an invaluable adjunct to current treatment options for HCV.
One of the major challenges facing the development of treatments or a vaccine for HCV is the high degree of genetic diversity that is exhibited by the virus, estimated to be 10 fold higher than that seen in HIV. Other factors that have hindered vaccine development for HCV include the lack of an accessible animal model and the fact that the virus cannot be easily grown in the laboratory. Although it may not be possible to develop a vaccine that targets all HCV genotypes, genotype specific vaccines that are administered in regions where specific genotypes dominate may be a realistic goal. Both T cell and antibody based vaccines to prevent and also to treat HCV infection are under development.
Further, a major challenge facing HCV infected patients that undergo liver transplants is recurrence of hepatitis C virus infection following otherwise technically successful liver transplantation. Recurrent HCV infection leads to diminished graft and patient survival. Although a number of predictors of severe recurrence have been identified, no definitive strategy has been developed to prevent recurrence. Although hepatitis B virus (HBV)-specific specific antibody products exist that are effective in preventing recurrence of HBV infection in liver transplant patients, no HCV-specific antibody is available yet for preventing recurrence of HCV infection in liver transplant patients. Currently, the only effective treatments for prevention of HCV recurrence after liver transplantation are interferon-based therapies, administered alone or in combination with ribavirin.
There remains a need in the art for more treatments of and vaccines to prevent HCV infection.